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Epilepsy Associated Depression: An Update on Current Scenario, Suggested Mechanisms, and Opportunities

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Abstract

Depression is one of the most frequent psychiatric comorbidities associated with epilepsy having a major impact on the patient’s quality of life. Several screening tools are available to identify and follow up psychiatric disorders in epilepsy. Out of various psychiatric disorders, people with epilepsy (PWE) are at greater risk of developing depression. This bidirectional relationship further hinders pharmacotherapy of comorbid depression in PWE as some antiepileptic drugs (AEDs) worsen associated depression and coadministration of existing antidepressants (ADs) to alleviate comorbid depression has been reported to worsen seizures. Selective serotonin reuptake inhibitors (SSRIs) and selective serotonin and norepinephrine reuptake inhibitors (SNRIs) are first choice of ADs and are considered safe in PWE, but there are no high-quality evidences. Similar to observations in people with depression, PWE also showed pharmacoresistant to available SSRI/SNRIs, which further complicates the disease prognosis. Randomized double-blind placebo-controlled clinical trials are necessary to report efficacy and safety of available ADs in PWE. We should also move beyond ADs, and therefore, we reviewed common pathological mechanisms such as neuroinflammation, dysregulated hypothalamus pituitary adrenal (HPA) axis, altered neurogenesis, and altered tryptophan metabolism responsible for coexistent relationship of epilepsy and depression. Based on these common pertinent pathways involved in the genesis of epilepsy and depression, we suggested novel targets and therapeutic approaches for safe management of comorbid depression in epilepsy.

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References

  1. Fisher RS, Acevedo C, Arzimanoglou A et al (2014) ILAE Official Report: a practical clinical definition of epilepsy. Epilepsia 55:475–482. https://doi.org/10.1111/epi.12550

    Article  PubMed  Google Scholar 

  2. Ngugi AK, Bottomley C, Kleinschmidt I et al (2010) Estimation of the burden of active and life-time epilepsy: a meta-analytic approach. Epilepsia 51:883–890. https://doi.org/10.1111/j.1528-1167.2009.02481.x

    Article  PubMed  PubMed Central  Google Scholar 

  3. Kanner AM (2016) Management of psychiatric and neurological comorbidities in epilepsy. Nat Rev Neurol 12:106–116. https://doi.org/10.1038/nrneurol.2015.243

    Article  CAS  PubMed  Google Scholar 

  4. Hermann B, Seidenberg M, Jones J (2008) The neurobehavioural comorbidities of epilepsy: can a natural history be developed? Lancet Neurol 7:151–160. https://doi.org/10.1016/S1474-4422(08)70018-8

    Article  PubMed  Google Scholar 

  5. Laxer KD, Trinka E, Hirsch LJ et al (2014) The consequences of refractory epilepsy and its treatment. Epilepsy Behav 37:59–70. https://doi.org/10.1016/j.yebeh.2014.05.031

    Article  PubMed  Google Scholar 

  6. Gill SJ, Lukmanji S, Fiest KM et al (2017) Depression screening tools in persons with epilepsy: a systematic review of validated tools. Epilepsia 58:695–705. https://doi.org/10.1111/epi.13651

    Article  PubMed  Google Scholar 

  7. Conway CR, Udaiyar A, Schachter SC (2018) Neurostimulation for depression in epilepsy. Epilepsy Behav 88:25–32. https://doi.org/10.1016/j.yebeh.2018.06.007

    Article  Google Scholar 

  8. Kwon OY, Park SP (2013) Frequency of affective symptoms and their psychosocial impact in Korean people with epilepsy: a survey at two tertiary care hospitals. Epilepsy Behav 26:51–56. https://doi.org/10.1016/j.yebeh.2012.10.020

    Article  PubMed  Google Scholar 

  9. Kanner AM, Schachter SC, Barry JJ et al (2012) Depression and epilepsy: epidemiologic and neurobiologic perspectives that may explain their high comorbid occurrence. Epilepsy Behav 24:156–168. https://doi.org/10.1016/j.yebeh.2012.01.007

    Article  PubMed  Google Scholar 

  10. Hesdorffer DC, Kanner AM (2009) The FDA alert on suicidality and antiepileptic drugs: fire or false alarm? Epilepsia 50:978–986. https://doi.org/10.1111/j.1528-1167.2009.02012.x

    Article  PubMed  Google Scholar 

  11. Hesdorffer DC, Berg AT, Kanner AM (2010) An update on antiepileptic drugs and suicide: are there definitive answers yet? Epilepsy Curr 10(6):137–145

    Article  Google Scholar 

  12. Gibbons RD, Hur K, Brown CH et al (2009) Relationship between antiepileptic drugs and suicide attempts in patients with bipolar disorder. Arch Gen Psychiatry 66:1354–1360

    Article  CAS  Google Scholar 

  13. Olesen JB, Hansen PR, Erdal J et al (2010) Antiepileptic drugs and risk of suicide: a nationwide study. Pharmacoepidemiol Drug Saf 19:518–524

    Article  Google Scholar 

  14. Patorno E, Bohn RL, Wahl PM et al (2010) Anticonvulsant medications and the risk of suicide, attempted suicide, or violent death. JAMA 303:1401–1409. https://doi.org/10.1001/jama.2010.410

    Article  CAS  PubMed  Google Scholar 

  15. VanCott AC, Cramer JA, Copeland LA et al (2010) Suicide-related behaviors in older patients with new anti-epileptic drug use: data from the VA hospital system. BMC Med 8:4. https://doi.org/10.1186/1741-7015-8-4

    Article  PubMed  PubMed Central  Google Scholar 

  16. Dreier JW, Pedersen CB, Gasse C et al (2019) Antiepileptic drugs and suicide: role of prior suicidal behavior and parental psychiatric disorder. Ann Neurol 86:951–961. https://doi.org/10.1002/ana.25623

    Article  PubMed  Google Scholar 

  17. Alper K, Schwartz KA, Kolts RL et al (2007) Seizure Incidence in psychopharmacological clinical trials: an analysis of food and drug administration (FDA) summary basis of approval reports. Biol Psychiatry 62:345–354. https://doi.org/10.1016/j.biopsych.2006.09.023

    Article  PubMed  Google Scholar 

  18. Hill T, Coupland C, Morriss R et al (2015) Antidepressant use and risk of epilepsy and seizures in people aged 20 to 64 years: Cohort study using a primary care database. BMC Psychiatry 15:1–13. https://doi.org/10.1186/s12888-015-0701-9

    Article  CAS  Google Scholar 

  19. Wu CS, Liu HY, Tsai HJ et al (2017) Seizure risk associated with antidepressant treatment among patients with depressive disorders: a population-based case-crossover study. J Clin Psychiatry 78:1226–1232

    Article  Google Scholar 

  20. Christensen J, Pedersen HS, Fenger-Grøn M et al (2019) Selective serotonin reuptake inhibitors and risk of epilepsy after traumatic brain injury—a population based cohort study. PLoS ONE 14:1–16. https://doi.org/10.1371/journal.pone.0219137

    Article  CAS  Google Scholar 

  21. Cardamone L, Salzberg MR, Koe AS et al (2014) Chronic antidepressant treatment accelerates kindling epileptogenesis in rats. Neurobiol Dis 63:194–200. https://doi.org/10.1016/j.nbd.2013.11.020

    Article  CAS  PubMed  Google Scholar 

  22. Li C, Silva J, Ozturk E et al (2018) Chronic fluoxetine treatment accelerates kindling epileptogenesis in mice independently of 5-HT2A receptors. Epilepsia 59:114–119. https://doi.org/10.1111/epi.14435

    Article  CAS  Google Scholar 

  23. Emamghoreishi M, Shahpari M, Keshavarz M (2019) Interaction of sigma-1 receptor modulators with seizure development in pentylenetetrazole-induced kindled mice. Epilepsy Res 154:74–76. https://doi.org/10.1016/j.eplepsyres.2019.05.001

    Article  CAS  PubMed  Google Scholar 

  24. Jiang Y, Pun RYK, Peariso K et al (2015) Olfactory bulbectomy leads to the development of epilepsy in mice. PLoS ONE 10:1–14. https://doi.org/10.1371/journal.pone.0138178

    Article  CAS  Google Scholar 

  25. Hoppe C, Elger CE (2011) Depression in epilepsy: a critical review from a clinical perspective. Nat Rev Neurol 7:462–472. https://doi.org/10.1038/nrneurol.2011.104

    Article  PubMed  Google Scholar 

  26. Ribot R, Ouyang B, Kanner AM (2017) The impact of antidepressants on seizure frequency and depressive and anxiety disorders of patients with epilepsy: is it worth investigating? Epilepsy Behav 70:5–9. https://doi.org/10.1016/j.yebeh.2017.02.032

    Article  PubMed  Google Scholar 

  27. Maguire MJ, Pulman J, Singh J et al (2013) Antidepressants for people with epilepsy and depression. Cochrane Database Syst Rev. https://doi.org/10.1002/14651858.CD010682

    Article  PubMed  Google Scholar 

  28. Harmant J, van Rijckevorsel-Harmant K et al (1990) Fluvoxamine: an antidepressant with low (or no) epileptogenic effect. Lancet 336:386

    Article  CAS  Google Scholar 

  29. Hovorka J, Herman E, Nemcová I (2000) Treatment of interictal depression with citalopram in patients with epilepsy. Epilepsy Behav 1:444–447. https://doi.org/10.1006/ebeh.2000.0123

    Article  PubMed  Google Scholar 

  30. Kühn KU, Quednow BB, Thiel M et al (2003) Antidepressive treatment in patients with temporal lobe epilepsy and major depression: a prospective study with three different antidepressants. Epilepsy Behav 4:674–679. https://doi.org/10.1016/j.yebeh.2003.08.009

    Article  PubMed  Google Scholar 

  31. Okazaki M, Adachi N, Ito M et al (2011) One-year seizure prognosis in epilepsy patients treated with antidepressants. Epilepsy Behav 22:331–335. https://doi.org/10.1016/j.yebeh.2011.07.016

    Article  PubMed  Google Scholar 

  32. Favale E, Rubino V, Mainardi P et al (1995) Anticonvulsant effect of fluoxetine in humans. Neurology 45:1926–1927. https://doi.org/10.1212/wnl.45.10.1926

    Article  CAS  PubMed  Google Scholar 

  33. Favale E, Audenino D, Cocito L et al (2003) The anticonvulsant effect of citalopram as an indirect evidence of serotonergic impairment in human epileptogenesis. Seizure 12:316–318. https://doi.org/10.1016/s1059-1311(02)00315-1

    Article  CAS  PubMed  Google Scholar 

  34. Gigli GL, Diomedi M, Troisi A et al (1994) Lack of potentiation of anticonvulsant effect by fluoxetine in drug-resistant epilepsy. Seizure 3:221–224. https://doi.org/10.1016/S1059-1311(05)80192-X

    Article  CAS  PubMed  Google Scholar 

  35. Kanner AM, Kozak AM, Frey M (2000) The use of sertraline in patients with epilepsy: is it safe? Epilepsy Behav 1:100–105. https://doi.org/10.1006/ebeh.2000.0050

    Article  PubMed  Google Scholar 

  36. Specchio LM, Iudice A, Specchio N et al (2004) Citalopram as treatment of depression in patients with epilepsy. Clin Neuropharmacol 27:133–136. https://doi.org/10.1097/00002826-200405000-00009

    Article  CAS  PubMed  Google Scholar 

  37. McKean J, Watts H, Mokszycki R (2015) Breakthrough seizures after starting vilazodone for depression. Pharmacotherapy 35:6–8. https://doi.org/10.1002/phar.1549

    Article  CAS  Google Scholar 

  38. Bielefeldt A, Danborg PB, Gøtzsche PC (2016) Precursors to suicidality and violence on antidepressants: systematic review of trials in adult healthy volunteers. J R Soc Med 109:381–392. https://doi.org/10.1177/0141076816666805

    Article  PubMed  PubMed Central  Google Scholar 

  39. Hernandez EJ, Williams PA, Dudek FE (2002) Effects of fluoxetine and TFMPP on spontaneous seizures in rats with pilocarpine-induced epilepsy. Epilepsia 43:1337–1345. https://doi.org/10.1046/j.1528-1157.2002.48701.x

    Article  CAS  PubMed  Google Scholar 

  40. Mazarati A, Siddarth P, Baldwin RA et al (2008) Depression after status epilepticus: behavioural and biochemical deficits and effects of fluoxetine. Brain 131:2071–2083. https://doi.org/10.1093/brain/awn117

    Article  PubMed  PubMed Central  Google Scholar 

  41. Vermoesen K, Massie A, Smolders I, Clinckers R (2012) The antidepressants citalopram and reboxetine reduce seizure frequency in rats with chronic epilepsy. Epilepsia 53:870–878. https://doi.org/10.1111/j.1528-1167.2012.03436.x

    Article  CAS  PubMed  Google Scholar 

  42. Sharma RK, Singh T, Mishra A et al (2017) Relative safety of different antidepressants for treatment of depression in chronic epileptic animals associated with depression. J Epilepsy Res 7:25–32. https://doi.org/10.14581/jer.17005

    Article  PubMed  PubMed Central  Google Scholar 

  43. Blumer D (1997) Antidepressant and double antidepressant treatment for the affective disorder of epilepsy. J Clin psychiatry 58:3. https://doi.org/10.4088/jcp.v58n0101

    Article  CAS  PubMed  Google Scholar 

  44. Robertson MM, Trimble MR (1985) The treatment of depression in patients with epilepsy. A double-blind trial. J Affect Disord 9:127–136. https://doi.org/10.1016/0165-0327(85)90091-6

    Article  CAS  PubMed  Google Scholar 

  45. Thome-Souza MS, Kuczynski E, Valente KD (2007) Sertraline and fluoxetine: safe treatments for children and adolescents with epilepsy and depression. Epilepsy Behav 10:417–425. https://doi.org/10.1016/j.yebeh.2007.01.004

    Article  CAS  PubMed  Google Scholar 

  46. Klein S, Bankstahl JP, Löscher W et al (2015) Sucrose consumption test reveals pharmacoresistant depression-associated behavior in two mouse models of temporal lobe epilepsy. Exp Neurol 263:263–271. https://doi.org/10.1016/j.expneurol.2014.09.004

    Article  CAS  PubMed  Google Scholar 

  47. Hesdorffer DC, Berg AT, Kanner AM (2010) An update on antiepileptic drugs and suicide: are there definitive answers yet? Epilepsy Curr 10:137–145. https://doi.org/10.1111/j.1535-7511.2010.01382.x

    Article  PubMed  PubMed Central  Google Scholar 

  48. Cardamone L, Salzberg MR, O’Brien TJ et al (2013) Antidepressant therapy in epilepsy: can treating the comorbidities affect the underlying disorder? Br J Pharmacol 168:1531–1554. https://doi.org/10.1111/bph.12052

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Kelley MS, Jacobs MP, Lowenstein DH (2009) The NINDS epilepsy research benchmarks. Epilepsia 50:579–582. https://doi.org/10.1111/j.1528-1167.2008.01813.x

    Article  PubMed  PubMed Central  Google Scholar 

  50. Vezzani A, French J, Bartfai T et al (2011) The role of inflammation in epilepsy. Nat Rev Neurol 7:31. https://doi.org/10.1038/nrneurol.2010

    Article  CAS  PubMed  Google Scholar 

  51. Marchi N, Granata T, Janigro D (2014) Inflammatory pathways of seizure disorders. Trends Neurosci 37:55–65. https://doi.org/10.1016/j.tins.2013.11.002

    Article  CAS  PubMed  Google Scholar 

  52. Rosenblat JD, Cha DS, Mansur RB et al (2014) Inflamed moods: a review of the interactions between inflammation and mood disorders. Prog Neuro-Psychopharmacology Biol Psychiatry 53:23–34. https://doi.org/10.1016/j.pnpbp.2014.01.013

    Article  CAS  Google Scholar 

  53. Elger CE, Johnston SA, Hoppe C (2017) Diagnosing and treating depression in epilepsy. Seizure 44:184–193. https://doi.org/10.1016/j.seizure.2016.10.018

    Article  PubMed  Google Scholar 

  54. Kanner AM, Mazarati A, Koepp M (2014) Biomarkers of epileptogenesis: psychiatric comorbidities (?). Neurotherapeutics 11:358–372. https://doi.org/10.1007/s13311-014-0271-4

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Mazarati AM, Lewis ML, Pittman QJ (2017) Neurobehavioral comorbidities of epilepsy: role of inflammation. Epilepsia 58:48–56. https://doi.org/10.1111/epi.13786

    Article  PubMed  Google Scholar 

  56. Vezzani A, Balosso S, Ravizza T (2019) Neuroinflammatory pathways as treatment targets and biomarkers in epilepsy. Nat Rev Neurol 15:459–472. https://doi.org/10.1038/s41582-019-0217-x

    Article  CAS  PubMed  Google Scholar 

  57. Arisi GM, Foresti ML, Katki K et al (2015) Increased CCL2, CCL3, CCL5, and IL-1β cytokine concentration in piriform cortex, hippocampus, and neocortex after pilocarpine-induced seizures. J Neuroinflammation 12:1–7. https://doi.org/10.1186/s12974-015-0347-z

    Article  CAS  Google Scholar 

  58. de Vries EE, van den Munckhof B, Braun KPJ et al (2016) Inflammatory mediators in human epilepsy: a systematic review and meta-analysis. Neurosci Biobehav Rev 63:177–190. https://doi.org/10.1016/j.neubiorev.2016.02.007

    Article  CAS  PubMed  Google Scholar 

  59. Ravizza T, Gagliardi B, Noé F et al (2008) Innate and adaptive immunity during epileptogenesis and spontaneous seizures: evidence from experimental models and human temporal lobe epilepsy. Neurobiol Dis 29:142–160. https://doi.org/10.1016/j.nbd.2007.08.012

    Article  CAS  PubMed  Google Scholar 

  60. Ravizza T, Vezzani A (2006) Status epilepticus induces time-dependent neuronal and astrocytic expression of interleukin-1 receptor type I in the rat limbic system. Neuroscience 137:301–308. https://doi.org/10.1016/j.neuroscience.2005.07.063

    Article  CAS  PubMed  Google Scholar 

  61. Henshall DC, Clark RSB, Adelson PD et al (2000) Alterations in bcl-2 and caspase gene family protein expression in human temporal lobe epilepsy. Neurology 55:250–257. https://doi.org/10.1212/WNL.55.2.250

    Article  CAS  PubMed  Google Scholar 

  62. Peng WF, Ding J, Li X et al (2016) N-methyl-d-aspartate receptor NR2B subunit involved in depression-like behaviours in lithium chloride-pilocarpine chronic rat epilepsy model. Epilepsy Res 119:77–85. https://doi.org/10.1016/j.eplepsyres.2015.09.013

    Article  CAS  PubMed  Google Scholar 

  63. Roseti C, van Vliet EA, Cifelli P et al (2015) GABAA currents are decreased by IL-1β in epileptogenic tissue of patients with temporal lobe epilepsy: Implications for ictogenesis. Neurobiol Dis 82:311–320. https://doi.org/10.1016/j.nbd.2015.07.003

    Article  CAS  PubMed  Google Scholar 

  64. Holtman L, van Vliet EA, van Schaik R et al (2009) Effects of SC58236, a selective COX-2 inhibitor, on epileptogenesis and spontaneous seizures in a rat model for temporal lobe epilepsy. Epilepsy Res 84:56–66. https://doi.org/10.1016/j.eplepsyres.2008.12.006

    Article  CAS  PubMed  Google Scholar 

  65. Tu B, Bazan NG (2003) Hippocampal kindling epileptogenesis upregulates neuronal cyclooxygenase-2 expression in neocortex. Exp Neurol 179:167–175. https://doi.org/10.1016/s0014-4886(02)00019-5

    Article  CAS  PubMed  Google Scholar 

  66. Rojas A, Jiang J, Ganesh T et al (2014) Cyclooxygenase-2 in epilepsy. Epilepsia 55:17–25. https://doi.org/10.1111/epi.12461

    Article  CAS  PubMed  Google Scholar 

  67. Zhu X, Yao Y, Yang J et al (2020) COX-2-PGE2 signaling pathway contributes to hippocampal neuronal injury and cognitive impairment in PTZ-kindled epilepsy mice. Int Immunopharmacol 87:106801. https://doi.org/10.1016/j.intimp.2020.106801

    Article  CAS  PubMed  Google Scholar 

  68. Singh T, Joshi S, Williamson JM et al (2020) (2020) Neocortical injury–induced status epilepticus. Epilepsia 61:2811–2824. https://doi.org/10.1111/epi.16715

    Article  CAS  PubMed  Google Scholar 

  69. Williamson J, Singh T, Kapur J (2019) Neurobiology of organophosphate-induced seizures. Epilepsy Behav 101:106426. https://doi.org/10.1016/j.yebeh.2019.07.027

    Article  PubMed  Google Scholar 

  70. Llorens-Martin M, Jurado-Arjona J, Bolos M et al (2016) Forced swimming sabotages the morphological and synaptic maturation of newborn granule neurons and triggers a unique pro-inflammatory milieu in the hippocampus. Brain Behav Immun 53:242–254

    Article  CAS  Google Scholar 

  71. Rossetti AC, Papp M, Gruca P et al (2016) Stress-induced anhedonia is associated with the activation of the inflammatory system in the rat brain: restorative effect of pharmacological intervention. Pharmacol Res 103:1–12

    Article  CAS  Google Scholar 

  72. Carboni L, Becchi S, Piubelli C et al (2010) Early-life stress and antidepressants modulate peripheral biomarkers in a gene-environment rat model of depression. Prog Neuropsychopharmacol Biol Psychiatry 34:1037–1048

    Article  CAS  Google Scholar 

  73. Dowlati Y, Herrmann N, Swardfager W et al (2010) A meta-analysis of cytokines in major depression. Biol Psychiatry 67:446–457. https://doi.org/10.1016/j.biopsych.2009.09.033

    Article  CAS  PubMed  Google Scholar 

  74. Köhler CA, Freitas TH, Maes M et al (2017) Peripheral cytokine and chemokine alterations in depression: a meta-analysis of 82 studies. Acta Psychiatr Scand 135:373–387. https://doi.org/10.1111/acps.12698

    Article  CAS  PubMed  Google Scholar 

  75. Citraro R, Leo A, Marra R et al (2015) Antiepileptogenic effects of the selective COX-2 inhibitor etoricoxib, on the development of spontaneous absence seizures in WAG/Rij rats. Brain Res Bull 113:1–7. https://doi.org/10.1016/j.brainresbull.2015.02.004

    Article  CAS  PubMed  Google Scholar 

  76. Li YC, Shen JD, Li J et al (2013) Chronic treatment with baicalin prevents the chronic mild stress-induced depressive-like behavior: Involving the inhibition of cyclooxygenase-2 in rat brain. Prog Neuro-Psychopharmacol Biol Psychiatry 40:138–143. https://doi.org/10.1016/j.pnpbp.2012.09.007

    Article  CAS  Google Scholar 

  77. Barbalho PG, Lopes-Cendes I, Maurer-Morelli CV (2016) Indomethacin treatment prior to pentylenetetrazole-induced seizures downregulates the expression of il1b and cox2 and decreases seizure-like behavior in zebrafish larvae. BMC Neurosci 17:1–9. https://doi.org/10.1186/s12868-016-0246-y

    Article  CAS  Google Scholar 

  78. Schlichtiger J, Pekcec A, Bartmann H et al (2010) Celecoxib treatment restores pharmacosensitivity in a rat model of pharmacoresistant epilepsy. Br J Pharmacol 160:1062–1071. https://doi.org/10.1111/j.1476-5381.2010.00765.x

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Zibell G, Unkruer B, Pekcec A et al (2009) Prevention of seizure-induced up-regulation of endothelial P-glycoprotein by COX-2 inhibition. Neuropharmacology 56:849–855

    Article  CAS  Google Scholar 

  80. Song TT, Li D, Huang SP et al (2016) Effects of cyclooxygenase-2 selective inhibitor celecoxib on the expression of major vault protein in rats with status epilepticus. Zhongguo Dang Dai Er Ke Za Zhi 18:440–445

    CAS  PubMed  Google Scholar 

  81. Liu B, Wang T, Wang L et al (2011) Up-regulation of major vault protein in the frontal cortex of patients with intractable frontal lobe epilepsy. J Neurol Sci 308:88–93

    Article  CAS  Google Scholar 

  82. Brooks AK, Lawson MA, Smith RA et al (2016) Interactions between inflammatory mediators and corticosteroids regulate transcription of genes within the Kynurenine Pathway in the mouse hippocampus. J Neuroinflammation 13:1–16. https://doi.org/10.1186/s12974-016-0563-1

    Article  CAS  Google Scholar 

  83. Xu ZH, Wang Y, Tao AF et al (2016) Interleukin-1 receptor is a target for adjunctive control of diazepam-refractory status epilepticus in mice. Neuroscience 328:22–29. https://doi.org/10.1016/j.neuroscience.2016.04.036

    Article  CAS  PubMed  Google Scholar 

  84. Kapur J, Macdonald RL (1997) Rapid seizure-induced reduction of benzodiazepine and Zn2+ sensitivity of hippocampal dentate granule cell GABAA receptors. J Neurosci 17:7532–7540. https://doi.org/10.1523/JNEUROSCI.17-19-07532.1997

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Hu F, Wang X, Pace TWW et al (2005) Inhibition of COX-2 by celecoxib enhances glucocorticoid receptor function. Mol Psychiatry 10:426–428. https://doi.org/10.1038/sj.mp.4001644

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Pineda EA, Hensler JG, Sankar R et al (2012) Interleukin-1beta Causes Fluoxetine resistance in an animal model of epilepsy-associated depression. Neurotherapeutics 9:477–485. https://doi.org/10.1007/s13311-012-0110-4

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Singh T, Goel RK (2016) Adjuvant indoleamine 2,3-dioxygenase enzyme inhibition for comprehensive management of epilepsy and comorbid depression. Eur J Pharmacol 784:111–120. https://doi.org/10.1016/j.ejphar.2016.05.019

    Article  CAS  PubMed  Google Scholar 

  88. Xie W, Cai L, Yu Y et al (2014) Activation of brain indoleamine 2,3-dioxygenase contributes to epilepsy-associated depressive-like behavior in rats with chronic temporal lobe epilepsy. J Neuroinflammation 11:41. https://doi.org/10.1186/1742-2094-11-41

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Mazarati AM, Pineda E, Shin D et al (2010) Comorbidity between epilepsy and depression: role of hippocampal interleukin-1beta. Neurobiol Dis 37:461–467. https://doi.org/10.1016/j.nbd.2009.11.001

    Article  CAS  PubMed  Google Scholar 

  90. Dilena R, Mauri E, Aronica E et al (2019) Therapeutic effect of Anakinra in the relapsing chronic phase of febrile infection–related epilepsy syndrome. Epilepsia open 2:344–350. https://doi.org/10.1002/epi4.12317

    Article  Google Scholar 

  91. Jyonouchi H, Geng L (2016) Intractable epilepsy (IE) and responses to Anakinra, a human recombinant IL-1 receptor antagonist (IL-1Ra): case reports. J Clin Cell Immunol 7:456–460. https://doi.org/10.4172/2155-9899.1000456

    Article  Google Scholar 

  92. DeSena AD, Do T, Schulert GS (2018) Systemic autoinflammation with intractable epilepsy managed with interleukin-1 blockade. J Neuroinflammation 15:38. https://doi.org/10.1186/s12974-018-1063-2

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Zeng LH, Rensing NR, Wong M (2009) The mammalian target of rapamycin signaling pathway mediates epileptogenesis in a model of temporal lobe epilepsy. J Neurosci 29:64–72. https://doi.org/10.1523/JNEUROSCI.0066-09.2009

    Article  CAS  Google Scholar 

  94. Bar-klein G, Cacheaux LP, Kamintsky L et al (2014) Losartan prevents acquired epilepsy via TGF-β signaling suppression. Ann Neurol 2014:864–875. https://doi.org/10.1002/ana.24147

    Article  CAS  Google Scholar 

  95. Zhang S, Zong Y, Ren Z et al (2020) Regulation of indoleamine 2, 3-dioxygenase in hippocampal microglia by NLRP3 inflammasome in lipopolysaccharide-induced depressive-like behaviors. Eur J Neurosci 52:4586–4601. https://doi.org/10.1111/ejn.15016

    Article  PubMed  Google Scholar 

  96. Singh P, Singh D, Goel RK (2014) Ficus religiosa L. figs—a potential herbal adjuvant to phenytoin for improved management of epilepsy and associated behavioral comorbidities. Epilepsy Behav 41:171–178. https://doi.org/10.1016/j.yebeh.2014.10.002

    Article  PubMed  Google Scholar 

  97. Singh T, Goel RK (2017) Adjuvant neuronal nitric oxide synthase inhibition for combined treatment of epilepsy and comorbid depression. Pharmacol Rep 69:143–149. https://doi.org/10.1016/j.pharep.2016.10.001

    Article  CAS  PubMed  Google Scholar 

  98. Singh T, Kaur T, Goel RK (2017) Adjuvant quercetin therapy for combined treatment of epilepsy and comorbid depression. Neurochem Int 104:27–33. https://doi.org/10.1016/j.neuint.2016.12.023

    Article  CAS  PubMed  Google Scholar 

  99. Singh T, Bagga N, Kaur A et al (2017) Agmatine for combined treatment of epilepsy, depression and cognitive impairment in chronic epileptic animals. Biomed Pharmacother 92:720–725. https://doi.org/10.1016/j.biopha.2017.05.085

    Article  CAS  PubMed  Google Scholar 

  100. Singh T, Kaur T, Goel RK (2017) Ferulic acid supplementation for management of depression in epilepsy. Neurochem Res 42:2940–2948. https://doi.org/10.1007/s11064-017-2325-6

    Article  CAS  PubMed  Google Scholar 

  101. Singh T, Goel RK (2017) Managing epilepsy-associated depression: Serotonin enhancers or serotonin producers? Epilepsy Behav 66:93–99. https://doi.org/10.1016/j.yebeh.2016.10.007

    Article  PubMed  Google Scholar 

  102. Campbell BM, Charych E, Lee AW et al (2014) Kynurenines in CNS disease: regulation by inflammatory cytokines. Front Neurosci 8:1–22. https://doi.org/10.3389/fnins.2014.00012

    Article  Google Scholar 

  103. Vécsei L, Szalárdy L, Fülöp F et al (2013) Kynurenines in the CNS: recent advances and new questions. Nat Rev Drug Discov 12:64–82. https://doi.org/10.1038/nrd3793

    Article  CAS  PubMed  Google Scholar 

  104. Lapin IP (1978) Stimulant and convulsive effects of kynurenines injected into brain ventricles in mice. J Neural Transm 42:37–43. https://doi.org/10.1007/BF01262727

    Article  CAS  PubMed  Google Scholar 

  105. Rios C, Santamaria A (1991) Quinolinic acid is a potent lipid peroxidant in rat brain homogenates. Neurochem Res 16:1139–1143. https://doi.org/10.1007/BF00966592

    Article  CAS  PubMed  Google Scholar 

  106. Santamaría A, Jiménez-Capdeville ME, Camacho A et al (2001) In vivo hydroxyl radical formation after quinolinic acid infusion into rat corpus striatum. NeuroReport 12:2693–2696. https://doi.org/10.1097/00001756-200108280-00020

    Article  PubMed  Google Scholar 

  107. Rodríguez-Martínez E, Camacho A, Maldonado PD et al (2000) Effect of quinolinic acid on endogenous antioxidants in rat corpus striatum. Brain Res 858:436–439. https://doi.org/10.1016/S0006-8993(99)02474-9

    Article  PubMed  Google Scholar 

  108. Vezzani A, Stasi MA, Wu HQ et al (1989) Studies on the potential neurotoxic and convulsant effects of increased blood levels of quinolinic acid in rats with altered blood-brain barrier permeability. Exp Neurol 106:90–98. https://doi.org/10.1016/0014-4886(89)90149-0

    Article  CAS  PubMed  Google Scholar 

  109. Nakano K, Takahashi S, Mizobuchi M et al (1993) High levels of quinolinic acid in brain of epilepsy-prone E1 mice. Brain Res 619:195–198. https://doi.org/10.1016/0006-8993(93)91612-V

    Article  CAS  PubMed  Google Scholar 

  110. Eastman CL, Urbańska E, Löve A et al (1994) Increased brain quinolinic acid production in mice infected with a hamster neurotropic measles virus. Exp Neurol 125:119–124

    Article  CAS  Google Scholar 

  111. Stone TW, Darlington LG (2002) Endogenous kynurenines as targets for drug discovery and development. Nat Rev Drug Discov 1:609–620. https://doi.org/10.1038/nrd870

    Article  CAS  PubMed  Google Scholar 

  112. Liimatainen S, Lehtimäki K, Raitala A et al (2011) Increased indoleamine 2,3-dioxygenase (IDO) activity in idiopathic generalized epilepsy. Epilepsy Res 94:206–212. https://doi.org/10.1016/j.eplepsyres.2011.02.003

    Article  CAS  PubMed  Google Scholar 

  113. Christmas DM, Potokar JP, Davies SJ (2011) A biological pathway linking inflammation and depression: activation of indoleamine 2, 3-dioxygenase. Neuropsychiatr Dis Treat 7:431. https://doi.org/10.2147/NDT.S17573

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. Suento WJ, Kunisawa K, Wulaer B et al (2020) Prefrontal cortex miR-874-3p prevents lipopolysaccharide-induced depression-like behavior through inhibition of indoleamine 2, 3-dioxygenase 1 expression in mice. J Neurochem. https://doi.org/10.1111/jnc.15222

    Article  PubMed  Google Scholar 

  115. Hazari N, Bhad R (2015) Kynurenine pathway (KP) inhibitors: Novel agents for the management of depression. J Psychopharmacol 29:1133–1134. https://doi.org/10.1177/0269881115599386

    Article  CAS  PubMed  Google Scholar 

  116. Wang DD, Englot DJ, Garcia PA et al (2012) Minocycline- and tetracycline-class antibiotics are protective against partial seizures in vivo. Epilepsy Behav 24:314–318. https://doi.org/10.1016/j.yebeh.2012.03.035

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. Wang N, Mi X, Gao B et al (2015) Minocycline inhibits brain inflammation and attenuates spontaneous recurrent seizures following pilocarpine-induced status epilepticus. Neuroscience 287:144–156. https://doi.org/10.1016/j.neuroscience.2014.12.021

    Article  CAS  PubMed  Google Scholar 

  118. Zheng LS, Kaneko N, Sawamoto K (2015) Minocycline treatment ameliorates interferon-alpha-induced neurogenic defects and depression-like behaviors in mice. Front Cell Neurosci 9:1–10. https://doi.org/10.3389/fncel.2015.00005

    Article  CAS  Google Scholar 

  119. Jiang T, Sun Y, Yin Z et al (2015) Research progress of indoleamine 2,3-dioxygenase inhibitors. Fut Med Chem 7:185–201. https://doi.org/10.4155/fmc.14.151

    Article  CAS  Google Scholar 

  120. Żarnowska I, Wróbel-Dudzińska D, Tulidowicz-Bielak M et al (2019) Changes in tryptophan and kynurenine pathway metabolites in the blood of children treated with ketogenic diet for refractory epilepsy. Seizure 69:265–272. https://doi.org/10.1016/j.seizure.2019.05.006

    Article  PubMed  Google Scholar 

  121. Maciejak P, Szyndler J, Turzyńska D et al (2009) Time course of changes in the concentration of kynurenic acid in the brain of pentylenetetrazol-kindled rats. Brain Res Bull 78:299–305. https://doi.org/10.1016/j.brainresbull.2008.10.010

    Article  CAS  PubMed  Google Scholar 

  122. Juda MB, Brooks AK, Towers AE et al (2019) Indoleamine 2,3-dioxygenase 1 deletion promotes Theiler’s virus–induced seizures in C57BL/6J mice. Epilepsia 60:626–635. https://doi.org/10.1111/epi.14675

    Article  CAS  PubMed  Google Scholar 

  123. Parrott JM, O’Connor JC (2015) Kynurenine 3-monooxygenase: an influential mediator of neuropathology. Front Psychiatry 6:1–17. https://doi.org/10.3389/fpsyt.2015.00116

    Article  Google Scholar 

  124. Haroon E, Raison CL, Miller AH (2012) Psychoneuroimmunology meets neuropsychopharmacology: translational implications of the impact of inflammation on behavior. Neuropsychopharmacology 37:137–162. https://doi.org/10.1038/npp.2011.205

    Article  CAS  PubMed  Google Scholar 

  125. Wu HQ, Rassoulpour A, Goodman JH et al (2005) Kynurenate and 7-chlorokynurenate formation in chronically epileptic rats. Epilepsia 46:1010–1016. https://doi.org/10.1111/j.1528-1167.2005.67404.x

    Article  CAS  PubMed  Google Scholar 

  126. Zhu WL, Wang SJ, Liu MM et al (2013) Glycine site N-methyl-D-aspartate receptor antagonist 7-CTKA produces rapid antidepressant-like effects in male rats. J Psychiatry Neurosci 38:306–316. https://doi.org/10.1503/jpn.120228

    Article  PubMed  PubMed Central  Google Scholar 

  127. Bin LB, Luo L, Liu XL et al (2015) 7-Chlorokynurenic acid (7-CTKA) produces rapid antidepressant-like effects: through regulating hippocampal microRNA expressions involved in TrkB-ERK/Akt signaling pathways in mice exposed to chronic unpredictable mild stress. Psychopharmacology 232:541–550. https://doi.org/10.1007/s00213-014-3690-3

    Article  CAS  Google Scholar 

  128. Zanos P, Piantadosi SC, Wu HQ et al (2015) The prodrug 4-chlorokynurenine causes ketamine-like antidepressant effects, but not side effects, by NMDA/glycineB-site inhibitionS. J Pharmacol Exp Ther 355:76–85. https://doi.org/10.1124/jpet.115.225664

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  129. Danzer SC (2012) Depression, stress, epilepsy and adult neurogenesis. Exp Neurol 233:22–32. https://doi.org/10.1016/j.expneurol.2011.05.023

    Article  PubMed  Google Scholar 

  130. Gage FH (2000) Mammalian neural stem cells. Science 287:1433–1438. https://doi.org/10.1126/science.287.5457.1433

    Article  CAS  PubMed  Google Scholar 

  131. Zhou M, Li W, Huang S et al (2013) mTOR inhibition ameliorates cognitive and affective deficits caused by disc1 knockdown in adult-born dentate granule neurons. Neuron 77:647–654. https://doi.org/10.1016/j.neuron.2012.12.033

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  132. Raijmakers M, Clynen E, Smisdom N et al (2016) Experimental febrile seizures increase dendritic complexity of newborn dentate granule cells. Epilepsia 57:717–726. https://doi.org/10.1111/epi.13357

    Article  CAS  PubMed  Google Scholar 

  133. Murphy BL, Pun RYK, Yin H et al (2011) Heterogeneous integration of adult-generated granule cells into the epileptic brain. J Neurosci 31:105–117. https://doi.org/10.1523/JNEUROSCI.2728-10.2011

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  134. Korn MJ, Mandle QJ, Parent JM (2016) Conditional disabled-1 deletion in mice alters hippocampal neurogenesis and reduces seizure threshold. Front Neurosci. https://doi.org/10.3389/fnins.2016.00063

    Article  PubMed  PubMed Central  Google Scholar 

  135. Singer BH, Gamelli AE, Fuller CL et al (2011) Compensatory network changes in the dentate gyrus restore long-term potentiation following ablation of neurogenesis in young-adult mice. Proc Natl Acad Sci U S A 108:5437–5442. https://doi.org/10.1073/pnas.1015425108

    Article  PubMed  PubMed Central  Google Scholar 

  136. Santos VR, de Castro OW, Pun RYK et al (2011) Contributions of mature granule cells to structural plasticity in temporal lobe epilepsy. Neuroscience 197:348–357. https://doi.org/10.1016/j.neuroscience.2011.09.034

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  137. Fang M, Xi ZQ, Wu Y, Wang XF (2011) A new hypothesis of drug refractory epilepsy: neural network hypothesis. Med Hypotheses 76:871–876. https://doi.org/10.1016/j.mehy.2011.02.039

    Article  CAS  PubMed  Google Scholar 

  138. Alenina N, Klempin F (2015) The role of serotonin in adult hippocampal neurogenesis. Behav Brain Res 277:49–57. https://doi.org/10.1016/j.bbr.2014.07.038

    Article  CAS  PubMed  Google Scholar 

  139. Jaako K, Aonurm-Helm A, Kalda A et al (2011) Repeated citalopram administration counteracts kainic acid-induced spreading of PSA-NCAM-immunoreactive cells and loss of reelin in the adult mouse hippocampus. Eur J Pharmacol 666:61–71. https://doi.org/10.1016/j.ejphar.2011.05.008

    Article  CAS  PubMed  Google Scholar 

  140. Jaako K, Zharkovsky T, Zharkovsky A (2009) Effects of repeated citalopram treatment on kainic acid-induced neurogenesis in adult mouse hippocampus. Brain Res 1288:18–28. https://doi.org/10.1016/j.brainres.2009.06.089

    Article  CAS  PubMed  Google Scholar 

  141. Cho KO, Lybrand ZR, Ito N et al (2015) Aberrant hippocampal neurogenesis contributes to epilepsy and associated cognitive decline. Nat Commun 6:1–13. https://doi.org/10.1038/ncomms7606

    Article  CAS  Google Scholar 

  142. Varma P, Brulet R, Zhang L et al (2019) Targeting seizure-induced neurogenesis in a clinically relevant time period leads to transient but not persistent seizure reduction. J Neurosci 39:7019–7028. https://doi.org/10.1523/JNEUROSCI.0920-19.2019

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  143. Arida RM, De Jesus VA, Cavalheiro EA (1998) Effect of physical exercise on kindling development. Epilepsy Res 30:127–132. https://doi.org/10.1016/S0920-1211(97)00102-2

    Article  CAS  PubMed  Google Scholar 

  144. Young D, Lawlor PA, Leone P et al (1999) Environmental enrichment inhibits spontaneous apoptosis, prevents seizures and is neuroprotective. Nat Med 5:448–453. https://doi.org/10.1038/7449

    Article  CAS  PubMed  Google Scholar 

  145. Setkowicz Z, Kosonowska E, Kaczyńska M et al (2016) Physical training decreases susceptibility to pilocarpine-induced seizures in the injured rat brain. Brain Res 1642:20–32. https://doi.org/10.1016/j.brainres.2016.03.008

    Article  CAS  PubMed  Google Scholar 

  146. Mishra V, Shuai B, Kodali M et al (2015) Resveratrol treatment after status epilepticus restrains neurodegeneration and abnormal neurogenesis with suppression of oxidative stress and inflammation. Sci Rep 5:1–19. https://doi.org/10.1038/srep17807

    Article  CAS  Google Scholar 

  147. Hester MS, Hosford BE, Santos VR et al (2016) Impact of rapamycin on status epilepticus induced hippocampal pathology and weight gain. Exp Neurol 280:1–12. https://doi.org/10.1016/j.expneurol.2016.03.015

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  148. Maguire J, Salpekar JA (2013) Stress, seizures, and hypothalamic-pituitary-adrenal axis targets for the treatment of epilepsy. Epilepsy Behav 26:352–362. https://doi.org/10.1016/j.yebeh.2012.09.040

    Article  PubMed  Google Scholar 

  149. O’Toole KK, Hooper A, Wakefield S et al (2014) Seizure-induced disinhibition of the HPA axis increases seizure susceptibility. Epilepsy Res 108:29–43. https://doi.org/10.1016/j.eplepsyres.2013.10.013

    Article  CAS  PubMed  Google Scholar 

  150. Kumar G, Couper A, O’Brien TJ et al (2007) The acceleration of amygdala kindling epileptogenesis by chronic low-dose corticosterone involves both mineralocorticoid and glucocorticoid receptors. Psychoneuroendocrinology 32:834–842. https://doi.org/10.1016/j.psyneuen.2007.05.011

    Article  CAS  PubMed  Google Scholar 

  151. Castro OW, Santos VR, Pun RYK et al (2012) Impact of corticosterone treatment on spontaneous seizure frequency and epileptiform activity in mice with chronic epilepsy. PLoS ONE 7:1–9. https://doi.org/10.1371/journal.pone.0046044

    Article  CAS  Google Scholar 

  152. Wulsin AC, Franco-Villanueva A, Romancheck C et al (2018) Functional disruption of stress modulatory circuits in a model of temporal lobe epilepsy. PLoS ONE 13:1–19. https://doi.org/10.1371/journal.pone.0197955

    Article  CAS  Google Scholar 

  153. Joëls M (2009) Stress, the hippocampus, and epilepsy. Epilepsia 50:586–597. https://doi.org/10.1111/j.1528-1167.2008.01902.x

    Article  PubMed  Google Scholar 

  154. MacKenzie G, Maguire J (2015) Chronic stress shifts the GABA reversal potential in the hippocampus and increases seizure susceptibility. Epilepsy Res 109:13–27. https://doi.org/10.1016/j.eplepsyres.2014.10.003

    Article  CAS  PubMed  Google Scholar 

  155. Berton O, Nestler EJ (2006) New approaches to antidepressant drug discovery: beyond monoamines. Nat Rev Neurosci 7:137–151. https://doi.org/10.1038/nrn1846

    Article  CAS  PubMed  Google Scholar 

  156. Chameau P, Qin Y, Spijker S et al (2007) Glucocorticoids specifically enhance L-type calcium current amplitude and affect calcium channel subunit expression in the mouse hippocampus. J Neurophysiol 97:5–14. https://doi.org/10.1152/jn.00821.2006

    Article  CAS  PubMed  Google Scholar 

  157. Culebras A, Miller M, Bertram L et al (1987) Differential response of growth hormone, cortisol, and prolactin to seizures and to stress. Epilepsia 28:564–570. https://doi.org/10.1111/j.1528-1157.1987.tb03689.x

    Article  CAS  PubMed  Google Scholar 

  158. Tunca Z, Ergene Ü, Fidaner H et al (2000) Reevaluation of serum cortisol in conversion disorder with seizure (pseudoseizure). Psychosomatics 41:152–153. https://doi.org/10.1176/appi.psy.41.2.152

    Article  CAS  PubMed  Google Scholar 

  159. Abbott RJ, Browning MCK, Davidson DLW (1980) Serum prolactin and cortisol concentrations after grand mal seizures. J Neurol Neurosurg Psychiatry 43:163–167. https://doi.org/10.1136/jnnp.43.2.163

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  160. Pritchard PB, Wannamaker BB, Sagel J (1985) Daniel CM (1985) Serum prolactin and cortisol levels in evaluation of pseudoepileptic seizures. Ann Neurol 18:87–89. https://doi.org/10.1002/ana.410180115

    Article  PubMed  Google Scholar 

  161. Galimberti CA, Magri F, Copello F et al (2005) Seizure frequency and cortisol and dehydroepiandrosterone sulfate (DHEAS) levels in women with epilepsy receiving antiepileptic drug treatment. Epilepsia 46:517–523. https://doi.org/10.1111/j.0013-9580.2005.59704.x

    Article  CAS  PubMed  Google Scholar 

  162. Jacobson L, Sapolsky R (1991) The role of the hippocampus in feedback regulation of the hypothalamic-pituitary-adrenocortical axis. Endocr Rev 12:118–134. https://doi.org/10.1210/edrv-12-2-118

    Article  CAS  PubMed  Google Scholar 

  163. Belzung C, Villemeur DEB (2010) The design of new antidepressants: Can formal models help? A first attempt using a model of the hippocampal control over the HPA-axis based on a review from the literature. Behav Pharmacol 21:677–689. https://doi.org/10.1097/FBP.0b013e328340d630

    Article  CAS  PubMed  Google Scholar 

  164. Herman JP, Cullinan WE (1997) Neurocircuitry of stress: central control of the hypothalamo-pituitary-adrenocortical axis. Trends Neurosci 20:78–84. https://doi.org/10.1016/S0166-2236(96)10069-2

    Article  CAS  PubMed  Google Scholar 

  165. Johnson SA, Fournier NM, Kalynchuk LE (2006) Effect of different doses of corticosterone on depression-like behavior and HPA axis responses to a novel stressor. Behav Brain Res 168:280–288. https://doi.org/10.1016/j.bbr.2005.11.019

    Article  CAS  PubMed  Google Scholar 

  166. Roberts AJ, Keith LD (1994) Sensitivity of the circadian rhythm of kainic acid-induced convulsion susceptibility to manipulations of corticosterone levels and mineralocorticoid receptor binding. Neuropharmacology 33:1087–1093. https://doi.org/10.1016/0028-3908(94)90147-3

    Article  CAS  PubMed  Google Scholar 

  167. Kling MA, Smith MA, Glowa JR et al (1993) Facilitation of cocaine kindling by glucocorticoids in rats. Brain Res 629:163–166. https://doi.org/10.1016/0006-8993(93)90497-B

    Article  CAS  PubMed  Google Scholar 

  168. Karst H (1999) Episodic corticosterone treatment accelerates kindling epileptogenesis and triggers long-term changes in hippocampal CA1 cells, in the fully kindled state. Eur J Neurosci 11:889–898. https://doi.org/10.1046/j.1460-9568.1999.00495.x

    Article  CAS  PubMed  Google Scholar 

  169. Mazarati AM, Shin D, Kwon YS et al (2009) Elevated plasma corticosterone level and depressive behavior in experimental temporal lobe epilepsy. Neurobiol Dis 34:457–461. https://doi.org/10.1016/j.nbd.2009.02.018

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  170. Koe AS, Jones NC, Salzberg MR (2009) Early life stress as an influence on limbic epilepsy: an hypothesis whose time has come? Front Behav Neurosci 3:1–16. https://doi.org/10.3389/neuro.08.024.2009

    Article  CAS  Google Scholar 

  171. Huang LT (2014) Early-life stress impacts the developing hippocampus and primes seizure occurrence: cellular, molecular, and epigenetic mechanisms. Front Mol Neurosci 7:1–15. https://doi.org/10.3389/fnmol.2014.00008

    Article  CAS  Google Scholar 

  172. Hanson ND, Owens MJ, Nemeroff CB (2011) Depression, antidepressants, and neurogenesis: a critical reappraisal. Neuropsychopharmacology 36:2589–2602. https://doi.org/10.1038/npp.2011.220

    Article  PubMed  PubMed Central  Google Scholar 

  173. Petrik D, Lagace DC, Eisch AJ (2012) The neurogenesis hypothesis of affective and anxiety disorders: are we mistaking the scaffolding for the building? Neuropharmacology 62:21–34. https://doi.org/10.1016/j.neuropharm.2011.09.003

    Article  CAS  PubMed  Google Scholar 

  174. Slotkin TA, Seidler FJ, Ritchie JC (1998) Effects of aging and glucocorticoid treatment on monoamine oxidase subtypes in rat cerebral cortex: therapeutic implications. Brain Res Bull 47:345–348. https://doi.org/10.1016/S0361-9230(98)00111-7

    Article  CAS  PubMed  Google Scholar 

  175. Karten YJG, Nair SM, Van Essen L et al (1999) Long-term exposure to high corticosterone levels attenuates serotonin responses in rat hippocampal CA1 neurons. Proc Natl Acad Sci USA 96:13456–13461. https://doi.org/10.1073/pnas.96.23.13456

    Article  CAS  PubMed  Google Scholar 

  176. Leitch MM, Ingram CD, Young AH et al (2003) Flattening the corticosterone rhythm attenuates 5-HT1A autoreceptor function in the rat: Relevance for depression. Neuropsychopharmacology 28:119–125. https://doi.org/10.1038/sj.npp.1300016

    Article  CAS  PubMed  Google Scholar 

  177. Kanner AM (2012) Can neurobiological pathogenic mechanisms of depression facilitate the development of seizure disorders? Lancet Neurol 11:1093–1102. https://doi.org/10.1016/S1474-4422(12)70201-6

    Article  CAS  PubMed  Google Scholar 

  178. Hooper A, Paracha R, Maguire J (2018) Seizure-induced activation of the HPA axis increases seizure frequency and comorbid depression-like behaviors. Epilepsy Behav 78:124–133. https://doi.org/10.1016/j.yebeh.2017.10.025

    Article  PubMed  Google Scholar 

  179. Dale E, Bang-Andersen B, Sánchez C (2015) Emerging mechanisms and treatments for depression beyond SSRIs and SNRIs. Biochem Pharmacol 95:81–97. https://doi.org/10.1016/j.bcp.2015.03.011

    Article  CAS  PubMed  Google Scholar 

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Singh, T., Goel, R.K. Epilepsy Associated Depression: An Update on Current Scenario, Suggested Mechanisms, and Opportunities. Neurochem Res 46, 1305–1321 (2021). https://doi.org/10.1007/s11064-021-03274-5

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